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Results: 141 to 148 of 148

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An essential role of Bmp4 in the atrioventricular septation of the mouse heart.
Jiao K, Kulessa H, Tompkins K, Zhou Y, Batts L, Baldwin HS, Hogan BL
(2003) Genes Dev 17: 2362-7
MeSH Terms: Animals, Animals, Newborn, Bone Morphogenetic Protein 4, Bone Morphogenetic Proteins, Gene Expression Regulation, Developmental, Heart, Heart Defects, Congenital, Mice, Mice, Mutant Strains, Mice, Transgenic, Myocytes, Cardiac, Signal Transduction, Transforming Growth Factor beta, Transforming Growth Factor beta2
Show Abstract · Added February 28, 2014
Proper septation and valvulogenesis during cardiogenesis depend on interactions between the myocardium and the endocardium. By combining use of a hypomorphic Bone morphogenetic protein 4 (Bmp4) allele with conditional gene inactivation, we here identify Bmp4 as a signal from the myocardium directly mediating atrioventricular septation. Defects in this process cause one of the most common human congenital heart abnormalities, atrioventricular canal defect (AVCD). The spectrum of defects obtained through altering Bmp4 expression in the myocardium recapitulates the range of AVCDs diagnosed in patients, thus providing a useful genetic model with AVCD as the primary defect.
2 Communities
1 Members
0 Resources
14 MeSH Terms
Glucose-6-phosphate dehydrogenase modulates cytosolic redox status and contractile phenotype in adult cardiomyocytes.
Jain M, Brenner DA, Cui L, Lim CC, Wang B, Pimentel DR, Koh S, Sawyer DB, Leopold JA, Handy DE, Loscalzo J, Apstein CS, Liao R
(2003) Circ Res 93: e9-16
MeSH Terms: Animals, Calcium, Cell Membrane, Cells, Cultured, Cytosol, Disease Models, Animal, Glucosephosphate Dehydrogenase, Glucosephosphate Dehydrogenase Deficiency, Male, Mice, Mice, Mutant Strains, Myocardial Contraction, Myocytes, Cardiac, Oxidants, Oxidation-Reduction, Phenotype, Protein Transport, Rats, Rats, Sprague-Dawley, Reactive Oxygen Species, Subcellular Fractions
Show Abstract · Added March 5, 2014
Reactive oxygen species (ROS)-mediated cell injury contributes to the pathophysiology of cardiovascular disease and myocardial dysfunction. Protection against ROS requires maintenance of endogenous thiol pools, most importantly, reduced glutathione (GSH), by NADPH. In cardiomyocytes, GSH resides in two separate cellular compartments: the mitochondria and cytosol. Although mitochondrial GSH is maintained largely by transhydrogenase and isocitrate dehydrogenase, the mechanisms responsible for sustaining cytosolic GSH remain unclear. Glucose-6-phosphate dehydrogenase (G6PD) functions as the first and rate-limiting enzyme in the pentose phosphate pathway, responsible for the generation of NADPH in a reaction coupled to the de novo production of cellular ribose. We hypothesized that G6PD is required to maintain cytosolic GSH levels and protect against ROS injury in cardiomyocytes. We found that in adult cardiomyocytes, G6PD activity is rapidly increased in response to cellular oxidative stress, with translocation of G6PD to the cell membrane. Furthermore, inhibition of G6PD depletes cytosolic GSH levels and subsequently results in cardiomyocyte contractile dysfunction through dysregulation of calcium homeostasis. Cardiomyocyte dysfunction was reversed through treatment with either a thiol-repleting agent (L-2-oxothiazolidine-4-carboxylic acid) or antioxidant treatment (Eukarion-134), but not with exogenous ribose. Finally, in a murine model of G6PD deficiency, we demonstrate the development of in vivo adverse structural remodeling and impaired contractile function over time. We, therefore, conclude that G6PD is a critical cytosolic antioxidant enzyme, essential for maintenance of cytosolic redox status in adult cardiomyocytes. Deficiency of G6PD may contribute to cardiac dysfunction through increased susceptibility to free radical injury and impairment of intracellular calcium transport. The full text of this article is available online at http://www.circresaha.org.
0 Communities
1 Members
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21 MeSH Terms
Cellular remodeling in heart failure disrupts K(ATP) channel-dependent stress tolerance.
Hodgson DM, Zingman LV, Kane GC, Perez-Terzic C, Bienengraeber M, Ozcan C, Gumina RJ, Pucar D, O'Coclain F, Mann DL, Alekseev AE, Terzic A
(2003) EMBO J 22: 1732-42
MeSH Terms: Adenosine Triphosphate, Animals, Calcium, Cardiac Output, Low, Cardiotonic Agents, Creatine Kinase, Dinitrophenols, Female, Ion Channel Gating, Isoproterenol, Male, Mice, Mitochondria, Myocardium, Myocytes, Cardiac, Patch-Clamp Techniques, Potassium Channels, Transforming Growth Factor alpha, Transgenes, Uncoupling Agents, Ventricular Remodeling
Show Abstract · Added February 21, 2015
ATP-sensitive potassium (K(ATP)) channels are required for maintenance of homeostasis during the metabolically demanding adaptive response to stress. However, in disease, the effect of cellular remodeling on K(ATP) channel behavior and associated tolerance to metabolic insult is unknown. Here, transgenic expression of tumor necrosis factor alpha induced heart failure with typical cardiac structural and energetic alterations. In this paradigm of disease remodeling, K(ATP) channels responded aberrantly to metabolic signals despite intact intrinsic channel properties, implicating defects proximal to the channel. Indeed, cardiomyocytes from failing hearts exhibited mitochondrial and creatine kinase deficits, and thus a reduced potential for metabolic signal generation and transmission. Consequently, K(ATP) channels failed to properly translate cellular distress under metabolic challenge into a protective membrane response. Failing hearts were excessively vulnerable to metabolic insult, demonstrating cardiomyocyte calcium loading and myofibrillar contraction banding, with tolerance improved by K(ATP) channel openers. Thus, disease-induced K(ATP) channel metabolic dysregulation is a contributor to the pathobiology of heart failure, illustrating a mechanism for acquired channelopathy.
0 Communities
1 Members
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21 MeSH Terms
The skeletal muscle ryanodine receptor isoform 1 is found at the intercalated discs in human and mouse hearts.
Jeyakumar LH, Gleaves LA, Ridley BD, Chang P, Atkinson J, Barnett JV, Fleischer S
(2002) J Muscle Res Cell Motil 23: 285-92
MeSH Terms: Animals, Antibodies, Calcium Signaling, Connexin 43, Fluorescent Antibody Technique, Humans, Male, Mice, Muscle Contraction, Muscle, Skeletal, Myocardium, Myocytes, Cardiac, Protein Isoforms, Ryanodine Receptor Calcium Release Channel, Subcellular Fractions
Show Abstract · Added February 21, 2016
The ryanodine receptors (RyRs) are a class of intracellular calcium release channels of which there are three isoforms. In striated muscle, isoform 1 and isoform 2 are mainly expressed in the terminal cisternae of sarcoplasmic reticulum of skeletal muscle and heart, respectively. Isoform 3 is widely distributed in tissues but in minuscule amounts. These channels release calcium ions from intracellular stores in excitation-contraction coupling for cell signaling. Here, we report the presence of skeletal muscle isoform 1 localized in the intercalated discs (IDs) of human and mouse hearts. By using RyR1 and connexin43 specific antibodies and dual immunofluorescent techniques, both were localized in the proximity of the IDs of human and mouse hearts. We confirmed that RyR1 is localized to the IDs by selective immunoprecipitation of RyR isoform 1 from a subcellular fraction containing IDs from human heart tissue. The functional significance of our observation remains to be elucidated as isoform 1 is involved in depolarization induced calcium release, unlike RyR isoforms 2 and 3 which appear to be involved in calcium induced calcium release.
0 Communities
1 Members
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15 MeSH Terms
Beta-adrenergic receptor-stimulated apoptosis in cardiac myocytes is mediated by reactive oxygen species/c-Jun NH2-terminal kinase-dependent activation of the mitochondrial pathway.
Remondino A, Kwon SH, Communal C, Pimentel DR, Sawyer DB, Singh K, Colucci WS
(2003) Circ Res 92: 136-8
MeSH Terms: Animals, Apoptosis, Bongkrekic Acid, Caspase Inhibitors, Catalase, Cells, Cultured, Cytochrome c Group, Enzyme Inhibitors, Free Radical Scavengers, Ion Channels, JNK Mitogen-Activated Protein Kinases, Metalloporphyrins, Mitochondria, Mitochondrial Membrane Transport Proteins, Mitogen-Activated Protein Kinases, Myocytes, Cardiac, Norepinephrine, Organometallic Compounds, Prazosin, Rats, Reactive Oxygen Species, Receptors, Adrenergic, beta, Salicylates, Signal Transduction
Show Abstract · Added March 5, 2014
Stimulation of beta-adrenergic receptors (betaARs) causes apoptosis in adult rat ventricular myocytes (ARVMs). The role of reactive oxygen species (ROS) in mediating betaAR-stimulated apoptosis is not known. Stimulation of betaARs with norepinephrine (10 micromol/L) in the presence of prazosin (100 nmol/L) for 24 hours increased the number of apoptotic myocytes as determined by TUNEL staining by 3.6- fold. The superoxide dismutase/catalase mimetics Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (MnTMPyP; 10 micromol/L) and Euk-134 decreased betaAR-stimulated apoptosis by 89+/-6% and 76+/-10%, respectively. Infection with an adenovirus expressing catalase decreased betaAR-stimulated apoptosis by 82+/-15%. The mitochondrial permeability transition pore inhibitor bongkrekic acid (50 micromol/L) decreased betaAR-stimulated apoptosis by 76+/-8%, and the caspase inhibitor zVAD-fmk (25 micromol/L) decreased betaAR-stimulated apoptosis by 62+/-11%. betaAR-stimulated cytochrome c release was inhibited by MnTMPyP. betaAR stimulation caused c-Jun NH2-terminal kinase (JNK) activation, which was abolished by MnTMPyP. Transfection with an adenovirus expressing dominant-negative JNK inhibited betaAR-stimulated apoptosis by 81+/-12%, and the JNK inhibitor SP600125 inhibited both betaAR-stimulated apoptosis and cytochrome c release. Thus, betaAR-stimulated apoptosis in ARVMs involves ROS/JNK-dependent activation of the mitochondrial death pathway.
0 Communities
1 Members
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24 MeSH Terms
Titin determines the Frank-Starling relation in early diastole.
Helmes M, Lim CC, Liao R, Bharti A, Cui L, Sawyer DB
(2003) J Gen Physiol 121: 97-110
MeSH Terms: Actin Cytoskeleton, Animals, Biomechanical Phenomena, Calcium, Cell Size, Connectin, Diastole, Heart Ventricles, In Vitro Techniques, Male, Muscle Proteins, Muscle, Skeletal, Myocardial Contraction, Myocytes, Cardiac, Protein Kinases, Rats, Rats, Wistar, Sarcomeres, Trypsin
Show Abstract · Added March 5, 2014
Titin, a giant protein spanning half the sarcomere, is responsible for passive and restoring forces in cardiac myofilaments during sarcomere elongation and compression, respectively. In addition, titin has been implicated in the length-dependent activation that occurs in the stretched sarcomere, during the transition from diastole to systole. The purpose of this study was to investigate the role of titin in the length-dependent deactivation that occurs during early diastole, when the myocyte is shortened below slack length. We developed a novel in vitro assay to assess myocyte restoring force (RF) by measuring the velocity of recoil in Triton-permeabilized, unloaded rat cardiomyocytes after rigor-induced sarcomere length (SL) contractions. We compared rigor-induced SL shortening to that following calcium-induced (pCa) contractions. The RF-SL relationship was linearly correlated, and the SL-pCa curve displayed a characteristic sigmoidal curve. The role of titin was defined by treating myocytes with a low concentration of trypsin, which we show selectively degrades titin using mass spectroscopic analysis. Trypsin treatment reduced myocyte RF as shown by a decrease in the slope of the RF-SL relationship, and this was accompanied by a downward and leftward shift of the SL-pCa curve, indicative of sensitization of the myofilaments to calcium. In addition, trypsin digestion did not alter the relationship between SL and interfilament spacing (assessed by cell width) after calcium activation. These data suggest that as the sarcomere shortens below slack length, titin-based restoring forces act to desensitize the myofilaments. Furthermore, in contrast to length-dependent activation at long SLs, length-dependent deactivation does not depend on interfilament spacing. This study demonstrates for the first time the importance of titin-based restoring force in length-dependent deactivation during the early phase of diastole.
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19 MeSH Terms
Overview of the Alliance for Cellular Signaling.
Gilman AG, Simon MI, Bourne HR, Harris BA, Long R, Ross EM, Stull JT, Taussig R, Bourne HR, Arkin AP, Cobb MH, Cyster JG, Devreotes PN, Ferrell JE, Fruman D, Gold M, Weiss A, Stull JT, Berridge MJ, Cantley LC, Catterall WA, Coughlin SR, Olson EN, Smith TF, Brugge JS, Botstein D, Dixon JE, Hunter T, Lefkowitz RJ, Pawson AJ, Sternberg PW, Varmus H, Subramaniam S, Sinkovits RS, Li J, Mock D, Ning Y, Saunders B, Sternweis PC, Hilgemann D, Scheuermann RH, DeCamp D, Hsueh R, Lin KM, Ni Y, Seaman WE, Simpson PC, O'Connell TD, Roach T, Simon MI, Choi S, Eversole-Cire P, Fraser I, Mumby MC, Zhao Y, Brekken D, Shu H, Meyer T, Chandy G, Heo WD, Liou J, O'Rourke N, Verghese M, Mumby SM, Han H, Brown HA, Forrester JS, Ivanova P, Milne SB, Casey PJ, Harden TK, Arkin AP, Doyle J, Gray ML, Meyer T, Michnick S, Schmidt MA, Toner M, Tsien RY, Natarajan M, Ranganathan R, Sambrano GR, Participating investigators and scientists of the Alliance for Cellular Signaling
(2002) Nature 420: 703-6
MeSH Terms: B-Lymphocytes, Cooperative Behavior, Databases, Factual, International Cooperation, Internet, Ligands, Models, Biological, Myocytes, Cardiac, Research, Research Design, Research Personnel, Signal Transduction, United States, Workforce
Show Abstract · Added March 21, 2013
The Alliance for Cellular Signaling is a large-scale collaboration designed to answer global questions about signalling networks. Pathways will be studied intensively in two cells--B lymphocytes (the cells of the immune system) and cardiac myocytes--to facilitate quantitative modelling. One goal is to catalyse complementary research in individual laboratories; to facilitate this, all alliance data are freely available for use by the entire research community.
0 Communities
1 Members
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14 MeSH Terms
TGFbeta regulates the expression of G alpha(i2) via an effect on the localization of ras.
Ward SM, Gadbut AP, Tang D, Papageorge AG, Wu L, Li G, Barnett JV, Galper JB
(2002) J Mol Cell Cardiol 34: 1217-26
MeSH Terms: Animals, Carbachol, Cardiotonic Agents, Cells, Cultured, Chick Embryo, Enzyme Inhibitors, Farnesol, GTP-Binding Protein alpha Subunit, Gi2, GTP-Binding Protein alpha Subunits, Gi-Go, Gene Expression Regulation, Developmental, Heart Atria, Heart Rate, Methionine, Myocytes, Cardiac, Parasympathetic Nervous System, Promoter Regions, Genetic, Proto-Oncogene Proteins, Transforming Growth Factor beta, ras Proteins
Show Abstract · Added February 21, 2016
The negative chronotropic response of the heart to parasympathetic stimulation is mediated via the interaction of M(2) muscarinic receptors, Galpha(i2) and the G-protein coupled inward rectifying K(+) channel, GIRK1. Here TGFbeta(1) is shown to decrease the expression of Galpha(i2) in cultured chick atrial cells in parallel with attenuation of the negative chronotropic response to parasympathetic stimulation. The response to the acetylcholine analogue, carbamylcholine, decreased from a 95+/-2% (+/-SEM, n=8) inhibition of beat rate in control cells to 18+/-2% (+/-SEM,n =8) in TGFbeta(1) treated cells. Data support the conclusion that TGFbeta regulation of Galpha(i2) expression was mediated via an effect on Ras. TGFbeta(1) inhibited Galpha(i2) promoter activity by 56+/-6% (+/-SEM, n=4) compared to control. A dominant activating Ras mutant reversed the effect of TGFbeta on Galpha(i2) expression and stimulated Galpha(i2) promoter activity 1.7 fold above control. A dominant negative Ras mutant mimicked the effect of TGFbeta(1) on Galpha(i2) promoter activity. TGFbeta had no effect on the ratio of GDP/GTP bound Ras, but markedly decreased the level of membrane associated Ras and increased the level of cytoplasmic Ras compared to control. Furthermore, farnesol, a precursor to farnesylpyrophosphate, the substrate for the farnesylation of Ras, not only reversed TGFbeta(1) inhibition of Ras localization to the membrane, but also reversed TGFbeta(1) inhibition of Galpha(i2)promoter activity. FTI-277, a specific inhibitor of the farnesylation of Ras, mimicked the effect of TGFbeta(1) on Ras localization and Galpha(i2) promoter activity. These data suggest a novel relationship between TGFbeta signaling, regulation of Ras function and the autonomic response of the heart.
0 Communities
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19 MeSH Terms